Role of the Brk tyrosine kinase in breast cancer progression

The Brk tyrosine kinase is expressed in approximately two-thirds of human breast carcinomas, including lymph node metastases, but neither in normal mammary tissue nor benign lesions. This study tested the hypothesis that Brk is involved in regulating the tumour cell environment during progression and investigated the effects of suppressing Brk in breast carcinoma cells to determine in which contexts Brk may be a valid therapeutic target.

We investigated whether Brk regulates the production of extracellular matrix enzymes and angiogenic cytokines, and whether Brk influences cell migration and chemotaxis. Studies to determine whether modification of Brk expression affects tumour behaviour in vivo are currently ongoing.

We have shown that suppression of Brk expression by RNA interference significantly decreases the secreted level of the matrix degrading enzyme MMP9 and the cytokine VEGFA, suggesting a role for Brk in regulating some of the processes involved in metastasis (proteolytic activity and neo-angiogenesis). As well as being able to modify the extracellular environment and to regulate angiogenic cytokine production, disseminating tumour cells must be able to survive in the circulation. We have also shown that Brk suppression increases the levels of cell death observed in breast carcinoma cells in suspension culture, implicating Brk in promoting anchorage-independent survival. In addition, suppression of Brk in suspension culture alters the relative levels of Bcl-x proteins in favour of Bcl-x_S. As elevated Bcl-x_L levels have been linked to chemotherapeutic resistance, targeting Brk may have benefits in overcoming chemoresistance in disseminating breast tumour cells.

Taken together these data propose key functions for Brk in breast tumour development and progression. Therapeutically targeting Brk may have multiple effects in controlling the spread of breast cancer.